Evidence-Based Approaches to Defer or Shorten Breast Radiotherapy during the COVID-19 Pandemic

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By Lior Braunstein, MD Erin Gillespie, MD Atif Khan, MD, MS on behalf of the Memorial Sloan Kettering research team

Breast radiation therapy

As governments and health authorities restrict in-person interactions to contain the spread of COVID-19, radiation oncologists must make unprecedented decisions on behalf of patients needing radiotherapy. We must balance the risk of presenting for treatment with being exposed to infection versus the benefit of the treatment itself, and consider if it is appropriate to omit, delay, or adopt accelerated schemes to optimize outcomes for patients. At the same time, we must protect our communities and scarce resources.

During the early days of the COVID-19 outbreak, a team of radiation oncologists specializing in breast cancer management at Memorial Sloan Kettering Cancer Center held contingency planning meetings with multidisciplinary experts across the institution. We reviewed the literature and established recommendations for the safe use of hypofractionated and abbreviated radiation regimens for our patients with breast cancer.

We found substantial evidence supporting strategies to omit radiation among favorable risk subgroups of patients with breast cancer and for abbreviating or accelerating regimens for others. Growing reports support hypofractionated approaches as safe and effective for patients who require either postmastectomy or whole-breast radiation, with or without coverage of regional lymph nodes.

We found substantial evidence supporting strategies to omit radiation among favorable risk subgroups of patients with breast cancer and for abbreviating or accelerating regimens for others.
Lior Z. Braunstein Assistant Attending Radiation Oncologist

Our review and recommended approaches for alleviating clinical burden without compromising oncologic outcomes during the COVID-19 pandemic are outlined in our paper, published recently in the journal Advances in Radiation Oncology. (1) The key points from our paper are summarized below:

Breast Radiotherapy and Resources

Breast radiotherapy has a varied benefit depending on the breast cancer presentation. For many indications, it is a curative aspect of treatment; for others, it has limited locoregional benefit without survival implications, such as with ductal carcinoma in situ (DCIS). (2)

The Centers for Disease Control and Prevention and the World Health Organization recommend limiting person-to-person interactions that are likely to occur among patients and healthcare staff in clinics during prolonged daily fractionation regimens. Additionally, healthcare resources in many centers may need to be repurposed for pandemic response, so limiting resource utilization becomes even more critical.

Therefore, in the setting of the COVID-19 pandemic, it is prudent to limit the overall use and duration of breast radiotherapy, given that we are operating under conditions of extreme resource constraints. Abbreviated fractionation regimens should be considered more strongly now than under typical practice conditions.

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Recommendations for Delaying or Omitting Breast Radiotherapy

Omitting Radiotherapy

These subgroups of low-risk patients have been studied in landmark trials that showed moderate local control with radiotherapy without improvement in the already excellent disease-specific survival outcomes:

  • DCIS: Radiotherapy among favorable DCIS presentations confers no survival benefit, as demonstrated in prospective observational studies (3) and randomized controlled trials. (4) Therefore, we advise forgoing radiotherapy for patients with lesions less than 2.5 centimeters (cm) in size as detected by a mammogram, of low or intermediate grade, and with greater than or equal to 2 millimeter (mm) resection margins. (5) Caution is recommended when deciding to forgo radiotherapy in patients under 40 years old. (6), (7)
  • Invasive disease: Omitting radiotherapy is preferred among patients 70 years old and older who have tumors that are estrogen receptor positive (ER+) and less than 3 cm, with no involved nodes and negative resection margins, (8) and who are eligible to receive endocrine therapy. (9) Lowering the threshold to age 65 may also be safe, according to a large study with more limited follow-up. (10) Ongoing studies for patients under 65 demonstrate equipoise with those who have biomarker-low disease, but no mature data exist yet. (11), (12)

Delaying Radiotherapy

Predicting future resource allocation is challenging during a public health emergency. Current estimates of population-level relief range from weeks to more than one year. (13), (14) To alleviate current constraints, evidence supports delaying radiotherapy for select patients with breast cancer as follows:

  • DCIS: Radiation can be safely delayed up to 12 weeks following breast-conserving surgery. (15)
  • Invasive disease: Patients with early-stage, node-negative, ER+ breast cancer can safely defer radiotherapy eight to 12 weeks after breast-conserving surgery without compromising disease control or survival. This recommendation is based on several large studies that showed a delay of up to 20 weeks is safe in select patients. (16), (17) Limited evidence is available to guide decision-making on the ideal interval from chemotherapy to radiotherapy. Most trials begin radiotherapy four to six weeks after chemotherapy. The large studies above suggest that an interval of up to 12 weeks may be reasonable.

Note that we recommend prompt initiation of endocrine therapy among eligible patients with ER+ breast cancer, either DCIS or invasive, who may experience a treatment delay or interruption. There is no evidence suggesting worse local control or survival with concurrent hormonal therapy, including both tamoxifen (18), (19) and aromatase inhibitors. (20) Subtle differences in breast edema, fibrosis or cosmesis, and lung toxicity have been reported, but the overall evidence is mixed. Therefore, the use of concurrent therapy should not be limited. (21)

Accelerated Partial-Breast Irradiation (APBI)

Several landmark prospective trials and a large body of literature have established the safety and efficacy of APBI among select patients. Most recurrences occur proximate to the tumor cavity, so treating the whole tumor bed with a margin confers outcomes similar to whole-breast radiotherapy in select settings. Further, using a smaller target volume allows us to accelerate the overall regimen from three to six weeks down to one to two weeks — a critical gain when resources are constrained. Patients may also benefit from reduced acute toxicity, as demonstrated by ten-year follow-up evidence of the Florence regimen of 30 gray (Gy) in five fractions, administered every other day. (22)

Note that the use of brachytherapy is discouraged when hospital resources are strained, especially as it increases opportunities for exposure and infection.

A variety of techniques and fractionation regimens are available for partial-breast radiation. There is a large body of evidence supporting APBI using three-dimensional conformal radiation therapy (3D-CRT) with 38.5 Gy in ten fractions delivered twice daily. (23), (24) Other well-supported options include 40 Gy in ten fractions daily using 3D-CRT (25), (26) and 30 Gy in five fractions every other day using intensity-modulated radiation therapy (IMRT). (23) Another effective option is 40 Gy in 15 daily fractions, although it is longer than the other APBI options. (27)

The American Society of Clinical Oncology consensus guidelines identify that APBI is suitable for patients with the following criteria: 50 years of age or older, with screen-detected invasive disease less than or equal to 2 mm in size that’s ER+ and node negative, or with DCIS that is of low or intermediate grade and is less than or equal to 2.5 cm in size. (28)

Whole-Breast Radiotherapy and Hypofractionated Regimens

Hypofractionation is already the preferred standard of care in the United States for patients who require whole-breast radiotherapy without nodal treatment. A number of fractionation schemes are well supported by evidence from clinical trials, including 42.56 Gy in 16 fractions (29) and 40 Gy in 15 fractions. (30)

Data is emerging for increased hypofractionation, such as 28.5 Gy in five once-weekly fractions (31) and an accelerated daily regimen of 26 Gy in five daily fractions. (32) While concerns about shorter regimens for whole-breast radiation have slowed widespread adoption, a number of prospective phase II, single-arm, and retrospective series have shown efficacy and safety among patients previously thought to be concerning: those with high-grade tumors, (33) with DCIS, (34) of a young age, (35) or with triple-negative breast cancer. (34)

Postmastectomy or Regional Nodal Irradiation

Two landmark studies, known as MA.20 and EORTC 22922, demonstrated that regional nodal irradiation reduces the risk of distant recurrence and significantly improves disease-free survival, even for patients with a limited axillary disease burden. (36), (37) As a result, more patients are now eligible for regional nodal irradiation following breast-conserving surgery or PMRT.

Unfortunately, hypofractionated nodal irradiation has not yet been widely adopted in the United States. Nascent literature suggests it is safe to use 40 Gy in 15 daily fractions targeting the breast or chest wall and regional nodes — presuming the supraclavicular hot spot is below 105 percent; otherwise 39 Gy in 15 fractions is preferred. (31), (38), (39), (40) Two ongoing studies, RT-CHARM (NCT03414970) and FABREC (NCT03422003), are further investigating three-week regimens.

Boost to the Tumor Bed

The use of boost radiotherapy is more limited in emergency settings.

  • DCIS: To date, the most extensive study evaluating the benefit of boost radiotherapy among patients with DCIS found a less than 2 percent local control benefit following whole-breast radiation. (41) In the absence of a survival benefit, boost radiotherapy should be omitted when resources are constrained. Caution is warranted, however, among patients younger than 40 years of age, in whom the approach was shown to improve local control by 10 percent at 72 months. (42)
  • Invasive disease: A tumor bed boost should only be considered following whole-breast radiation for patients with significant local recurrence risk factors: those who are 60 years of age, have high-grade tumors, or have inadequate margins. (43)

A standard boost after hypofractionated whole-breast irradiation is four to six fractions. However, evidence shows that a simultaneous integrated boost may be as safe and effective. (44), (45) When ultra-hypofractionation with five-fraction regimens is used, it is reasonable to consider one or two 5.2 Gy fractions to the tumor bed, with the caveat that this schedule has not been reported beyond the brachytherapy setting. (46)

Patients receiving whole-breast and nodal irradiation in a simultaneous integrated boost can reduce treatment visits. This treatment can be provided via IMRT or volumetric modulated arc radiotherapy but is also possible by delivering a supplemental electron field with each 3D-CRT fraction.

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Patient Prioritization

During the COVID-19 pandemic, it may be necessary to prioritize which patients with breast cancer receive radiotherapy. Priority should be provided to patients for whom a survival benefit is anticipated.

Based on the available evidence and emerging clinical judgment, we defined tiers of priority to guide decision-making around resource allocation. Note that prioritization among patients within each tier is left to the discretion of the treating physician and should include consideration of the patient’s age, risk of exposure, and predicted benefit of radiotherapy.

Table: Prioritization of Radiation Therapy (RT) for Breast Cancer Based on Indication (1)

Tier 1

High priority for breast RT

Inflammatory breast cancer

Residual node positivity after NAC

Four or more positive nodes (N2)[KB2] 

Recurrent disease

Node-positive TNBC

Extensive LVI

Tier 2

Intermediate priority for breast RT

ER+ with one to three positive nodes (N1a)[KB3] 

Path N0[KB4]  after NAC

LVI (NOS[KB5] )

Node-negative TNBC

Tier 3

Low priority for breast RT

Early-stage ER+, especially older patients

DCIS

Otherwise not meeting criteria for tiers 1 or 2

Abbreviations: Neoadjuvant chemotherapy (NAC), triple-negative breast cancer (TNBC), lymphovascular invasion (LVI).

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Advancing Cancer Care During the COVID-19 Pandemic

At MSK, the health and safety of our patients and staff is our top priority. Many of our researchers and clinicians are an essential part of the international response to the COVID-19 pandemic. We continue to collaborate across multiple disciplines to deliver excellent, evidence-based care for our patients.

MSK is offering a twice-weekly scientific seminar series, MSK Science Spotlight, featuring lectures by leaders in basic and translational biomedical science. The hour-long seminars are available by livestream on Mondays and Wednesdays at ET. No registration is required. Check out the schedule or watch past seminars here.

The authors listed above report no relevant conflicts of interest. For disclosures from other authors, refer to the paper.

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